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At least 91 records · Page 5Linked to original sources
PubMed2003

Gene transfer: regulatory issues and their impact on the clinical investigator and the good manufacturing production facility.

The first human gene-transfer study was submitted to the Recombinant DNA Advisory Committee (RAC) in 1988, thus initiating a new era in clinical research. As per the RAC Website (last updated 22nd November 2002), almost 550 human gene-transfer studies have been submitted to the RAC. However, there are currently no licensed gene-therapy products available in the USA. The natural evolution of the review process to accommodate these novel protocols, as well as the death of Jesse Gelsinger in 1999, have led to significant changes in the initial and ongoing review of gene-transfer studies. However, the basic framework of the review process remains unchanged.Gene-transfer protocols require oversight by the Food and Drug Administration (FDA), the Recombinant DNA Advisory Committee (RAC), the Institutional Biosafety Committee (IBC), and the Institutional Review Board (IRB). Such oversight includes both initial review of the protocol and ongoing review of the study through the review of annual reports, adverse events, and proposed amendments to the study. In addition to such review of the protocol, the product itself is required by the FDA to be prepared under current good manufacturing practices (cGMP). This article discusses both regulatory oversight and current GMP issues in depth.

Biological Products↗
PubMed2005

Response of retinoblastoma with vitreous tumor seeding to adenovirus-mediated delivery of thymidine kinase followed by ganciclovir.

PURPOSE: To evaluate the feasibility and safety of adenovirus-mediated gene therapy as a treatment for tumor seeds in the vitreous of children with retinoblastoma. PATIENTS AND METHODS: An Institutional Biosafety Committee-, Institutional Review Board-, Recombinant DNA Advisory Committee-, and US Food and Drug Administration-approved phase I study used intrapatient dose escalation of adenoviral vector containing a herpes simplex thymidine kinase gene (AdV-TK) followed by systemic administration of ganciclovir to treat bilateral retinoblastoma with vitreous tumor seeding refractory to standard therapies. Vitreous tumor seeds were treated by intravitreous injection of AdV-TK adjacent to disease sites. Each injection was followed by ganciclovir delivered intravenously every 12 hours for 7 days. RESULTS: Eight patients with vitreous tumor seeds were enrolled. One patient who was treated with 10(8) viral particles (vp) had resolution of the tumor seeds around the injection site. The seven patients who were treated with doses > or = 10(10) vp had resolution of their vitreous tumor seeds documented by fundoscopy. Toxicity included mild inflammation at 10(10) vp and moderate inflammation, corneal edema, and increased intraocular pressure at 10(11) vp. One patient was free of active vitreous tumor seeds 38 months after therapy. There has been no evidence of extraocular spread of tumor along the needle tract in any patient. CONCLUSION: AdV-TK followed by ganciclovir can be administered safely to children with retinoblastoma. Suicide gene therapy may contribute to the treatment of children with retinoblastoma tumor seeds in the vitreous, a resistant complication of retinoblastoma.

Adenoviruses, Human↗
PubMed2003

The National Institutes of Health system for enhancing the science, safety, and ethics of recombinant DNA research.

Oversight of recombinant DNA research by the National Institutes of Health (NIH) is predicated on ethical and scientific responsibilities that are akin, in many ways, to those that pertain to the oversight of animal research. The NIH system of oversight, which originated more than 25 years ago, is managed by the NIH Office of Biotechnology Activities (OBA), which uses various tools to fulfill its oversight responsibilities. These tools include the NIH Guidelines for Research Involving Recombinant DNA Molecules (NIH Guidelines) and the Recombinant DNA Advisory Committee. The OBA also undertakes special initiatives to promote the analysis and dissemination of information key to our understanding of recombinant DNA, and in particular, human gene transfer research. These initiatives include a new query-capable database, an analytical board of scientific and medical experts, and conferences and symposia on timely scientific, safety, and policy issues. Veterinary scientists can play an important role in the oversight of recombinant DNA research and in enhancing our understanding of the many safety and scientific dimensions of the field. These roles include developing appropriate animal models, reporting key safety data, enhancing institutional biosafety review, and promoting compliance with the NIH Guidelines.

Animal Welfare↗
PubMed1995

Gene therapy for the respiratory manifestations of cystic fibrosis.

Cystic fibrosis (CF) is caused by mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The major manifestations are on the airway epithelial surface, with purulent mucus, recurrent infections, chronic inflammation, and loss of lung function. Consequent to mutations in both parental genes, airway epithelial cells have insufficient CFTR function. Because this can be corrected in vitro by transfer of the normal CFTR gene into airway epithelial cells, it is reasonable to hypothesize that the respiratory manifestations of CF could be prevented by transfer of the normal human CFTR cDNA to the airway epithelium in vivo. Over the past 6 years, our laboratory has developed a strategy to accomplish this goal using a replication deficient E1-E3- recombinant adenovirus (Ad) serotype 5 vector containing the normal human CFTR cDNA (AdCFTR). Studies with experimental animals demonstrate that with administration of such a vector to the airways, the human CFTR cDNA could be transferred to the airway epithelium, with expression of the human CFTR cDNA for at least 6 weeks. Extensive preclinical studies in vitro and in vivo demonstrated that the risks to humans were sufficiently low to initiate a Phase I trial using the AdCFTR vector to treat the respiratory manifestations of CF in humans. Following approval by the National Heart, Lung, and Blood Institute Institutional Review Board, the National Institutes of Health Biosafety Committee, the National Institutes of Health Recombinant DNA Advisory Committee, and the Food and Drug Administration, we initiated the first human trial of gene therapy for CF on April 17, 1993. The clinical study is still ongoing, with safety and efficacy data being evaluated, but there is clear evidence that it is feasible to transfer and express the normal CFTR cDNA to the airway epithelium in vivo in individuals with CF.

Adenoviridae↗
PubMed1993

Human gene therapy: a biopolitical overview and analysis.

The benefits, risks, and social consequences arising from human gene therapy have received substantial citation in the literatures of medical, biological, ethical, and legal commentary. I argue that the question of what "public policy garb" best fits the parameters of human gene therapy in the United States and around the world is a quintessential political question, best understood under the microscope of political science analytic inquiry. I describe the nature of that inquiry, apply its insights to the various ends and means of human gene therapy, and posit empirical models of "political success" for the salient purposes of the craft. I focus particularly on the tract record of the National Institutes of Health's Recombinant DNA Advisory Committee (RAC) in orchestrating the process by which human gene therapy protocols achieve official sanction.

Advisory Committees↗
PubMed1991

Human gene therapy: ethics and public policy.

The first three human gene transfer/therapy clinical protocols are now underway after having been subjected to an extensive review process by the Recombinant DNA Advisory Committee (RAC) and its Human Gene Therapy Subcommittee. The "Points to Consider" document developed by the RAC established the framework for evaluating genetic intervention protocols. This review process is taking place in a broader social context. Public attitude surveys in this country have indicated a general lack of knowledge in the area of genetic engineering but an acceptance of somatic-cell gene therapy as treatment for disease. Internationally, numerous policy statements on human genetic intervention have been published, all of which support the moral legitimacy of somatic-cell gene therapy for the cure of disease. The debate over the ethical issues related to somatic-cell gene therapy has evolved over a ten-year-period. The time has now come to begin a formal public process for the ethical assessment of germ-line genetic intervention.

Advisory Committees↗
PubMed1993

Relationship between safety data and biocontainment design in the environmental assessment of fermentation organisms--an FDA perspective.

The Center for Veterinary Medicine requires strain/construct-specific data for recombinant fermentation organisms used in the production of animal drugs and feed additives. Fermentation plant biocontainment schemes are chosen based, in part, upon the ability of the organism to survive and persist in the environment and to transfer genetic information to indigenous organisms. Survival and persistence study methods may include one of the following ecosystems: activated sludge, mammalian gut, soil or river water. Gene transfer protocols can be incorporated into a persistence study. These studies are designed to show that the recombinant construct behaves similarly to the host in a representative ecosystem where the organism could be introduced inadvertently. The studies need to provide repeatable results and reflect current state-of-art design and methods. Data verification is conducted by FDA investigators during Good Laboratory Practice inspections. Biocontainment guidelines, such as those developed by the NIH Recombinant DNA Advisory Committee, set general biocontainment goals for large groupings of recombinant organisms. The FDA, as required under the National Environmental Policy Act, must base its decision making on verifiable scientific data specific to each application. Therefore, in addition to using these guidelines as benchmarks, sponsors are required to submit strain/construct-specific data to support the selection of an appropriate biocontainment level. Once additional well-controlled studies for a variety of constructs are available, broader generalizations as to biocontainment may be drawn.

Containment of Biohazards↗
PubMed2004

Ethics, regulation, and biomedical research.

Controversy has surrounded the institutions that facilitate discussion and regulation of American biomedical research for years. Recent challenges to the legitimacy of the President's Council on Bioethics have been focused on stem cell research. These arguments represent an opportunity to reconsider the legislation under which stem cell research is regulated, as well as to consider preexisting bodies like the Recombinant DNA Advisory Committee and National Bioethics Advisory Commission. This paper proposes a Federal Life Sciences Policy Commission, a novel commission with advisory and regulatory powers that would benefit from the positive and negative lessons learned under the legislation that currently shapes the formation and institutional characteristics of advisory bodies in the United States. The Federal Life Sciences Policy Commission would have institutional independence not present in previous advisory bodies, while maintaining the tradition of broad societal representation and thoughtful discourse that has developed in the United States.

Advisory Committees↗
PubMedDate not supplied

Development of the National Institutes of Health Guidelines for Recombinant DNA Research.

Recombinant DNA is a technique of major importance in basic biomedical research and, increasingly, in industrial applications. Although the risks of this research remain hypothetical, scientists working in the field have spearheaded discussions of safety. The original National Institutes of Health (NIH) Guidelines for Recombinant DNA Research were issued in June 1976. They assigned each type of recombinant DNA experiment a specific level of "physical containment" and of "biological containment." Responsibility for overseeing the application of the guidelines belongs to the NIH Recombinant DNA Advisory Committee (RAC)--composed of scientists and laymen, including non-voting representatives from many Federal agencies--and local institutional biosafety committees at each university where recombinant DNA research is conducted. The NIH guidelines were subsequently adopted by other Federal agencies, but congressional proposals aimed at extending the guidelines to private industry did not result in national legislation. Some States and localities regulate recombinant DNA research, however, and many private companies have voluntarily submitted information on their recombinant DNA work for RAC and NIH approval. The NIH guidelines underwent a major revision in December 1978 and have been revised approximately every 3 months since then. NIH supports experiments to assess recombinant DNA risks and publishes and updates a plan for a risk assessment program.

Containment of Biohazards↗
PubMed1996

Gene Replacement Strategies for Lung Cancer.

Advances in our understanding of the molecular genetics of cancer present an opportunity to develop prevention and treatment strategies based on the reversal of specific genetic lesions. This strategy is analogous to the classic concept of gene therapy for replacement of defective or nonfunctioning genes. The gene families implicated in carcinogenesis include dominant oncogenes and tumor suppressor genes. Regional administration of viral vectors expressing wildtype p53 and antisense K-ras prevents tumor growth for tumors with the specific genetic lesions in orthotopic tumor models and mediates regression of large established tumors. These studies provide a rationale for a new clinical protocol recently approved by the National Institutes of Health Recombinant DNA Advisory Committee and Food and Drug Administration to replace a defective p53 gene with intratumor injection of recombinant retrovirus expressing wild-type p53 or elimination of activated K-ras by expression of antisense K-ras messenger RNA. If these agents are efficacious, their lack of toxicity may provide a sufficiently high therapeutic index such that they could be used as an adjuvant to surgery to treat patients with earlier stages of cancer or as prevention for second primary cancers for individuals with genetic abnormalities in premalignant lesions. Although much research needs to be done, the possibility of specific gene targeting with a high therapeutic index makes this a promising area of investigation.

Journal Article↗
PubMed1996

Gene replacement strategies for cancer.

The strategy for the inactivation or replacement of cancer-causing genes is analogous to the classic concept of gene therapy for replacement of defective or nonfunctioning genes. The gene families implicated in carcinogenesis include dominant oncogenes and tumor suppressor genes. Regional administration of viral vectors expressing wildtype p53 and antisense K-ras prevents growth for tumors with the specific genetic lesions in orthotopic tumor models and mediates regression of large established tumors. These studies provide a rationale for a new clinical protocol recently approved by the United States National Institutes of Health (NIH) Recombinant DNA Advisory Committee and the Federal Drug Administration (FDA) to replace a defective p53 gene with intratumor injection of recombinant retrovirus expressing normal p53 and to inactivate mutant K-ras by expression of antisense K-ras mRNA. If these agents are efficacious, their lack of toxicity may provide a sufficiently high therapeutic index such that they could be used as an adjuvant to surgery to treat patients with earlier stages of cancer or as prevention for second primary cancers for individuals with genetic abnormalities in premalignant lesions. Although much research needs to be done, the possibility of specific gene targeting with a high therapeutic index makes this a promising area for investigation.

Genes, Tumor Suppressor↗